Synthesis of four stereoisomers of protected 1,2-epiimino-3- hydroxypropylphosphonates

Article abstract of DOI:10.1016/j.tetasy.2011.01.005

Enantiomerically pure protected 1,2-epiimino-3-hydroxypropylphosphonates were synthesised from hydroxy-1-{[(R)- or (S)-1-phenylethyl]aziridin-2-yl} methylphosphonates via regioselective ring opening with acetic acid followed by a stereospecific intramolec

Full text of DOI:10.1016/j.tetasy.2011.01.005

Tetrahedron: Asymmetry 22 (2011) 200–206
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of four stereoisomers of protected
1,2-epiimino-3-hydroxypropylphosphonates
⇑
Andrzej E. Wróblewski , Joanna Drozd
´
´
´
Bioorganic Chemistry Laboratory, Faculty of Pharmacy, Medical University of Łódz, 90-151 Łódz, Muszynskiego 1, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 December 2010
Accepted 12 January 2011
Enantiomerically pure protected 1,2-epiimino-3-hydroxypropylphosphonates were synthesised from
hydroxy-1-{[(R)- or (S)-1-phenylethyl]aziridin-2-yl}methylphosphonates via regioselective ring opening
with acetic acid followed by a stereospecific intramolecular cyclisation of 3-acetoxy-1-mesyloxy-2-(1-
phenylethyl)aminopropylphosphonates and hydrogenolytic removal of the 1-phenylethyl group in the
presence of Boc2O. The trans-isomers of 3-acetoxy-[N-(1-phenylethyl)-1,2-epiimino]propylphosphonates
exist as a 2:1 mixture of invertomers, which were fully structurally characterised based on their 1H and
1
13C NMR spectroscopic data. Large differences in the JC–P values in N-(1-phenylethyl)aziridine-2-phos-
phonates were noticed depending on the spatial arrangement of the nitrogen lone pair and the phospho-
rus atom (syn-periplanar—ca. 215 Hz; anti-periplanar—182 Hz).
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
In comparison to the numerous synthetic approaches to aziridine-
2-carboxylates, enantiomerically pure aziridine-2-phosphonates are
Several natural products with an aziridine ring, such as
mitomycins, azinomycins and porfiromycins show antitumor
activity.1,2 Other natural aziridines, also known as aziridine alka-
loids, display antibacterial and antimicrobial activity against se-
lected microorganisms.3 Even simple compounds, such as (2S,3S)-
aziridine-2,3-dicarboxylic acid 1, exhibited antibacterial activity.4
Peptides containing aziridine-2-carboxylic acid 2 or (2S,3S)-aziri-
dine-2,3-dicarboxylic acid 1 seem to be inhibitors of various prote-
ases.5–7 Aziridine-2-phosphonates 3 (R = R0 = R00 = H, alkyl) have
been claimed to show antibacterial properties (Fig. 1).8
less accessible.28 They can be prepared by the intramolecular cyclisa-
tion of
a
-hydroxy-b-aminoalkylphosphonates;29–31 a Darzens-type
condensation of imines with the anion of enantiopure bicyclic chloro-
methylphosphonamide;32 the addition of anions of haloge-
nmethylphosphonates to enantiomerically pure N-sulfinimines;33–36
the reduction of homochiral 2H-azirinephosphonates;37 the
addition of selected nucleophiles to azirine-3-phosphonates38–41
or by an aziridination of vinylphosphonates.42,43
In a continuation of our studies on the transformations of the
readily available hydroxy-1-{[(R) or (S)-1-phenylethyl]aziridin-2-
yl}methylphosphonates 444 into functionalised aminohydroxy-
phosphonates,45 we herein report an efficient route to all four
enantiomerically pure 1,2-epiiminopropylphosphonates 5 via the
corresponding acetates 6 (Scheme 1). Based on the literature
data,46–52 regioselective opening oftheaziridine ringinphosphonates
4 was expected to occur at the less substituted carbon atom.
CO2R"
H
N
H
N
N
P(O)(OR')2
R
HOOC
COOH
COOH
1
2
3
Figure 1. Examples of low-molecular weight bioactive aziridines.
2. Results and discussion
Interest in the chemistry of aziridines has significantly increased
in recent years due to numerous applications of these reactive small
heterocycles in the synthesis of various natural products,2,9–14
drugs15–18 and drug candidates.19–24 Procedures for the asymmetric
synthesis of non-racemic aziridines have been reviewed.2,25,26 In
general, they rely on either asymmetric transformations of either a
C@N or C@C bonds or application of the ‘chiron approach’.27
To obtain enantiomerically pure 2,3-disubstituted azi-
ridinephosphonates (2R,3S)-11a and (2S,3R)-11b (cis configured
isomers), phosphonates (1S,2S,10R)-7a44 and (1R,2R,10S)-7b44 were
selected as starting materials. The treatment of these compounds
with 3 equiv of glacial acetic acid in methylene chloride at room
temperature required 36 h for the reaction to go to completion.
However, refluxing the reaction mixture allowed us to shorten
the reaction time to 9 h. After chromatographic purification, phos-
phonate (1S,2S,10R)-8a and its enantiomer (1R,2R,10S)-8b were ob-
tained in 89% and 86% yields, respectively (Scheme 2 and 3).
⇑
Corresponding author. Tel.: +48 42 677 92 33; fax: +48 42 678 83 98.
E-mail address: andrzej.wroblewski@umed.lodz.pl (A.E. Wróblewski).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.01.005

A. E. Wróblewski, J. Drozd / Tetrahedron: Asymmetry 22 (2011) 200–206
201
*
R
NHR*
R
N
N
AcO
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
AcO
OH
OH
5
6
4
Scheme 1. Retrosynthesis of 1,2-epiiminopropylphosphonates.
Ph
NH
Me
Ph
H
Boc
N
Me
H
AcO
H
N
b
c
AcOH2C
H
P(O)(OEt)2
a
AcOH2C
H
P(O)(OEt)2
H
P(O)(OEt)2
H
Me
N
P(O)(OEt)2
H
OR
OH
(1S,2S,1'R)-7a
Ph
(2R,3S)-11a
(2R,3S,1'R)-10a
(1S,2S,1'R)-8a R=H
(1S,2S,1'R)-9a R=Ms
b
Scheme 2. Reagents and conditions: (a) AcOH, CH2Cl2, reflux, 9 h, 89%; (b) MsCl, NEt3, CH2Cl2, ꢀ70 °C to rt, overnight, 93%; (c) H2, 10% Pd–C, (Boc)2O, EtOH, rt, 7 h, 89%.
Ph
H
Ph
Me
H
Me
Boc
N
NH
N
H
c
b
a
H
H
H
H
AcO
P(O)(OEt)2
N
P(O)(OEt)2
Me
H
AcOH2C
P(O)(OEt)2
AcOH2C
P(O)(OEt)2
OR
OH
Ph
(1R,2R,1'S)-7b (ent-7a)
(2S,3R)-11b (ent-11a)
(1R,2R,1'S)-8b R=H
(1R,2R,1'S)-9b R=Ms
(2S,3R,1'S)-10b
b
Scheme 3. Reagents and conditions: (a) AcOH, CH2Cl2, reflux, 9 h, 86%; (b) MsCl, NEt3, CH2Cl2, ꢀ70 °C to rt, overnight, 92%; (c) H2, 10% Pd–C, (Boc)2O, EtOH, rt, 7 h, 89%.
The cyclisation of 1-hydroxypropylphosphonates 8a and 8b to
1,2-epiiminopropylphosphonates 10a and 10b was explored next.
This was achieved by the mesylation of the hydroxy group at low
temperature (ꢀ70 °C) followed by warming up the reaction mix-
ture to room temperature to carry out an aziridine ring closure.
The syn-isomers (1S,2S,10R)-8a and (1R,2R,10S)-8b were readily
transformed to cis-2,3-disubstituted aziridinephosphonates
(2R,3S,10R)-10a and (2S,3R,10S)-10b as single products in 93% and
92% yields, respectively (Scheme 2 and 3). The formation of cis-
configured aziridines 10a and 10b was unequivocally proven by
the observation of the vicinal H–H coupling constant (6.3 Hz) char-
acteristic of the cis-arrangement within the H–C2–C3–H moiety in
aziridines.49,53,54 The latter reaction proceeded completely via
intramolecular SN2 displacement and reflects the ability of the
mesylates (1S,2S,10R)-9a and (1R,2R,10S)-9b to adopt a conforma-
tion in which the substituted amine as a nucleophile and the leav-
ing group are antiperiplanar (Fig. 2).
formation of N-Boc-aziridine-2-phosphonates (2R,3S)-11a and
(2S,3R)-11b is expected. However, under these conditions the azi-
ridine ring opening could also be envisioned.30 Initially, the reac-
tion was attempted on phosphonate (2S,3R,10S)-10b in the
presence of a Pearlman’s catalyst in ethanol. After 24 h, a complex
reaction mixture was formed. Only small quantities of the impure
2-N-Boc-amino-3-acetoxypropylphosphonate (R)-12b were sepa-
rated from the reaction mixture (Fig. 3).
NHBoc
P(O)(OEt)2
NHBoc
P(O)(OEt)2
AcO
AcO
(S)-12a
(R)-12b
Figure 3. Side products obtained in the hydrogenation of phosphonates (2R,3S,10R)-
10a and (2S,3R,10S)-10b.
When the hydrogenation was carried out on phosphonate
(2R,3S,10R)-10a in the presence of a 1:1 mixture of Pd(OH)2–C
and 10% Pd–C for 72 h, a complex reaction mixture was again ob-
tained. However, the formation of N-Boc-aziridinephosphonate
(2R,3S)-11a (ca. 50%), phosphonate (S)-12a (ca. 10%) and several
unidentified phosphonates (d 31P 23.1–23.7 ppm) was confirmed
by the 31P NMR spectroscopy. The application of 10% Pd–C alone
as a catalyst in the hydrogenation of (2R,3S,10R)-10a afforded a
91:9 mixture of cis-aziridinephosphonate (2R,3S)-11a and phos-
phonate (S)-12a within 7 h. From this mixture, pure phosphonate
(2R,3S)-11a was separated chromatographically in 89% yield. Un-
der the same conditions, from aziridinephosphonate (2S,3R,10S)-
10b, N-Boc-aziridinephosphonate (2S,3R)-11b was also obtained
in 89% yield.
*
R
H
N
H
H
P(O)(OEt)2
CH2OAc
(1S,2S,1'R)-8a
(2R,3S,1'R)-10a
OMs
(1S,2S,1'R)-9a
Figure 2. An aziridine ring closure in mesylate (1S,2S,10R)-9a.
During the catalytic hydrogenation of aziridinephosphonates
(2R,3S,10R)-10a and (2S,3R,10S)-10b in the presence of Boc2O the

202
A. E. Wróblewski, J. Drozd / Tetrahedron: Asymmetry 22 (2011) 200–206
In a conceptually similar manner, the syntheses of trans-config-
*
R
H
ured aziridinephosphonates (2S,3S)-11c and (2R,3R)-11d were per-
formed. Refluxing aziridinephosphonate (1R,2S,10R)-7c44 with
3 equiv of acetic acid in CH2Cl2 for 9 h led to the formation of a
mixture which contained ca. 50% of phosphonate (1R,2S,10R)-8c to-
gether with the starting material (ca. 20%) and several unidentified
impurities as judged from the 31P NMR spectrum of the crude
product. Extension of the reaction time resulted in complete con-
sumption of the substrate, but led to the formation of significant
amounts of unidentified impurities. However, a total conversion
of phosphonate (1R,2S,10R)-7c was achieved when the reaction
was carried out in neat acetic acid at room temperature for 96 h.
After chromatographic purification, phosphonate (1R,2S,10R)-8c
was obtained in 61% yield (Scheme 4). In a similar fashion the azi-
ridinephosphonate (1S,2R,10S)-7d44 was transformed into phos-
phonate (1S,2R,10S)-8d in 62% yield (Scheme 5).
N
(EtO)2(O)P
H
(2S,3S,1'R)-10c
(1R,2S,1'R)-8c
CH2OAc
H
OMs
(1R,2S,1'R)-9c
Figure 4. An aziridine ring closure in mesylate (1R,2S,10R)-9c.
into a 2:1 mixture of N-invertomers of trans-aziridine-2-phospho-
nate (2R,3R,10S)-10d, also in 90% yield (Scheme 5).
Detailed analysis of the 1H and 13C NMR spectroscopic data of
trans-1,2-epiiminopropylphosphonate (2S,3S,10R)-10c revealed
that structures (1R,2S,3S,10R)-13c and (1S,2S,3S,10R)-13c can be as-
signed to the major and minor invertomers, respectively (Fig. 5).
In assigning structures (1R,2S,3S,10R)-13c to the major and
(1S,2S,3S,10R)-13c to the minor invertomer, the 13C NMR data were
of primary importance. Since the acetoxymethyl group in the ma-
jor invertomer does not spatially interact with any other substitu-
ent, the chemical shift of CH2OAc was found in a lower field (d
66.3 ppm) when compared to chemical shifts of these carbons in
the minor invertomer (d 60.1 ppm) and the cis-isomer
(2R,3S,10R)-10a (d 63.7 ppm) where the CH2OAc groups are close
to the 1-phenylethyl and diethoxyphosphoryl groups, respectively
(Fig. 5). Furthermore, the resonances of the stereogenic carbons in
the 1-phenylethyl groups in the major (d 60.8 ppm) as well as in
the minor (d 61.8 ppm) invertomers are significantly shifted up-
field as a result of the spatial proximity of these groups with the
diethoxyphosphoryl and acetoxymethyl groups, respectively,
when compared to the chemical shifts of C*HMePh in the cis iso-
mer 10a (d 71.4 ppm) and in the starting phosphonates 7a–7d (d
69–70 ppm).44
When the propylphosphonate (1R,2S,10R)-8c was subjected to
the standard two-step intramolecular cyclisation, two products in
a 2:1 ratio were formed as judged from the 31P NMR spectrum of
the crude reaction mixture (d 23.82 ppm and 22.59 ppm, respec-
tively). The 1H and 13C NMR spectra were also supportive since
two sets of signals in the same ratio were observed. None of the com-
pounds formed was identical with the already described cis isomers
10a and 10b. Because cyclisation of anti isomer (1R,2S,10R)-8c pro-
ceeded again via an intramolecular SN2 displacement (Fig. 4), only
trans-1,2-epiiminopropylphosphonate (2S,3S,10R)-10c should be
formed. However, 1,2,3-trisubstituted trans-aziridines are known
to exist as mixtures of invertomers49,57–61 due to the slow nitrogen
inversion on the NMR time scale. A chromatographic purification
of the reaction mixture obtained from the propylphosphonate
(1R,2S,10R)-8c gave an inseparable 2:1 mixture of N-invertomers
(2S,3S,10R)-10c in 90% yield (Scheme 4). Their 1H and 31P NMR spec-
tral data perfectly matched those observed for the compounds pres-
ent in the crude reaction mixture. The values of vicinal H–C2–C3–H
couplings found in both invertomers (3.6 and 2.7 Hz, respectively)
served as a direct proof of the trans configuration.49,53,54 In a similar
manner, the propylphosphonate (1S,2R,10S)-8d was transformed
The cis/trans relationships of the substituents in the trans
[(1R,2S,3S,10R)-13c and (1S,2S,3S,10R)-13c] and cis [(2R,3S,10R)-10a]
Ph
Me
Ph
H
Me
Ph
Boc
NH
H
AcO
Me
H
N
N
c
a
b
AcOH2C
H
H
AcOH2C
H
H
P(O)(OEt)2
N
P(O)(OEt)2
H
P(O)(OEt)2
P(O)(OEt)2
OR
OH
(1R,2S,1'R)-7c
(2S,3S,1'R)-10c
(2S,3S)-11c
(1R,2S,1'R)-8c R=H
(1R,2S,1'R)-9c R=Ms
b
Scheme 4. Reagents and conditions: (a) AcOH, rt, 4 d, 61%; (b) MsCl, NEt3, CH2Cl2, ꢀ70 °C to rt, overnight, 90%; (c) H2, 10% Pd–C, (Boc)2O, EtOH, rt, 7 h, 87%.
Ph
H
Ph
Boc
N
Me
H
Me
Ph
NH
H
Me
H
N
c
a
b
H
P(O)(OEt)2
H
AcO
P(O)(OEt)2
H
P(O)(OEt)2
H
N
P(O)(OEt)2
AcOH2C
AcOH2C
(2R,3R,1'S)-10d
OR
OH
(1S,2R,1'S)-7d (ent-7c)
(2R,3R)-11d (ent-11c)
(1S,2R,1'S)-8d R=H
(1S,2R,1'S)-9d R=Ms
b
Scheme 5. Reagents and conditions: (a) AcOH, rt, 4 d, 62%; (b) MsCl, NEt3, CH2Cl2, ꢀ70 °C to rt, overnight, 90%; (c) H2, 10% Pd–C, (Boc)2O, EtOH, rt, 7 h, 86%.

A. E. Wróblewski, J. Drozd / Tetrahedron: Asymmetry 22 (2011) 200–206
203
H
H
O
AcO
AcO
H3C
C
H
C
H
O
H
H
O
P
C
OEt
H
H
H
Me
H
N
N
C
Me
H
Me
H
C
C
O
OCH2CH3
H
H
H
N
P
O
C H2
CH3
O
H2C
H3C
P(O)(OEt)2
(1R,2R,3S,1'R)-10a
(1R,2S,3S,1'R)-13c
(1S,2S,3S,1'R)-13c
Figure 5. Structures of the invertomers of cis- and trans-1,2-epiiminopropylphosphonates (2R,3S,10R)-10a and (2S,3S,10R)-10c showing spatial interactions important for
stereochemical assignments (in red—upfield shifts of CH2OAc; in green—upfield shifts of C*HMePh; in blue—upfield shifts induced by aromatic ring currents).
aziridines can also be assigned by taking advantage of the shielding
effects that originate from the aromatic ring currents of the phenyl
groups in 1-phenylethyl residues.55,56 Thus, in the major invertomer
(1R,2S,3S,10R)-13c, the proton resonances of CH3 (d 0.84 ppm) and
CH2 (d 3.36–3.49 ppm and 3.53–3.65 ppm) groups in one of the
CH3CH2OP residues are significantly shifted upfield in comparison
to the other ethoxy group (d 1.26 ppm and d 3.96–4.07 ppm) and
to the entire diethoxyphosphoryl group in the minor invertomer
(1S,2S,3S,10R)-13c (d 1.26 and 1.36 ppm and d 4.05 and 4.20 ppm).
Similar shielding of the ethoxy group is observed in the cis-isomer
(2R,3S,10R)-10a (d 1.01 ppm and d 3.51 and 3.78 ppm). A significant
upfield shift of the CH3CO resonance in the minor invertomer (d
1.62 ppm) when compared to those in the major one (d 2.09 ppm)
and in the cis-isomer 10a (d 2.12 ppm) is also configurationally diag-
nostic and reflects the cis- and trans-orientations of the acetoxy-
methyl and 1-phenylethyl groups, respectively (Fig. 5).
less substituted carbon atom, low temperature mesylation fol-
lowed by an aziridine ring closure when reaching room tempera-
ture and the hydrogenolytic removal of the 1-phenylethyl
residue with simultaneous protection of the amino group as an
N-Boc derivative. The cis-isomers of the final N-Boc-aziridine-2-
phosphonates were obtained in higher overall yields than the
respective trans-isomers.
As expected, the inversion at the nitrogen atom was not observed
for the cis-isomers of N-(1-phenylethyl)aziridine-2-phosphonates.
However, the trans-isomers of N-(1-phenylethyl)aziridine-2-phos-
phonates exist as a 2:1 mixture of invertomers, which were fully
structurally characterised based on the 1H and 13C NMR spectro-
scopic data.
It was noticed that the spatial arrangement of the nitrogen lone
1
pair and the phosphorus atom has a strong influence on the JC–P
values in N-(1-phenylethyl)aziridine-2-phosphonates (for synperi-
planar—ca. 215 Hz; for antiperiplanar—182 Hz). To establish a
diagnostic value for these observations further studies are under
way in this laboratory.
The differences of the 13C NMR chemical shifts of C–P but espe-
cially of the one-bond C–P coupling constants in aziridine-2-phos-
phonates described herein, are noteworthy. When the nitrogen
lone pair is syn-periplanar to the phosphorus atom as in the minor
invertomer (1S,2S,3S,10R)-13c and in the cis-isomer (2R,3S,10R)-10a,
4. Experimental
1
C–P resonates at d 36.2 and 36.1 ppm and JC–P reaches 217.4 and
The 1H NMR spectra were recorded with a Varian Mercury-300
spectrometer; chemical shifts d in ppm with respect to TMS; cou-
pling constants J in hertz (Hz). 13C and 31P NMR spectra were
214.8 Hz, respectively. In the opposite case (anti-periplanar orien-
tation of the nitrogen lone pair and the phosphorus atom) as in the
major invertomer (1R,2S,3S,10R)-13c, C–P is shifted upfield (d
33.7 ppm) and 1JC–P drops down to 182.0 Hz. However, it appeared
that in cis- and trans-N-Boc-aziridinephosphonates (2R,3S)-11a
and (1S,2S)-11c one-bond C–P coupling constants are less differen-
tiated (207.4 and 197.7 Hz, respectively) and this observation re-
flects resonance stabilisation of the nitrogen lone pair into the
amide bond. Our conclusions regarding dependence of 1JC–P in azi-
ridine-2-phosphonates on the spatial orientation of the phospho-
rus atom and the nitrogen lone pair gained some support from
the literature precedences29,35,36,38,43 but its full diagnostic value
requires further validation.
recorded on
a Varian Mercury-300 machine at 75.5 and
121.5 MHz, respectively. The NMR characterisation of a mixture of
N-invertomers (1R,2S,3S,10R)-13c and (1S,2S,3S,10R)-13c was sup-
ported by 1H NMR, COSY and HMQC spectra taken on a Bruker
Avance III (600 MHz) spectrometer. IR spectral data were measured
on an Infinity MI-60 FT-IR spectrometer. Elemental analyses were
performed by the Microanalytical Laboratory of this Faculty on a
Perkin Elmer PE 2400 CHNS analyser. Polarimetric measurements
were conducted on a Optical Activity PolAAr 3001 apparatus. The
following absorbents were used: column chromatography, Merck
Silica Gel 60 (70ꢀ230 mesh); analytical TLC, Merck TLC plastic
Finally, the hydrogenolysis (10% Pd–C) of mixtures of N-inver-
tomers (2S,3S,10R)-10c and (2R,3R,10S)-10d gave 1,2-epi-
iminopropylphosphonates (1S,2S)-11c and (1R,2R)-11d in 87%
and 86% yields, respectively.
sheets Silica Gel 60 F254
.
4.1. Ring opening of aziridinephosphonates 7 with AcOH
(general procedure)
3. Conclusions
A solution of phosphonates 7a and 7b (0.313 g, 1.00 mmol) in
methylene chloride (4 mL) containing acetic acid (0.172 mL,
3.00 mmol) was refluxed for 9 h or a solution of phosphonates 7c
and 7d (0.313 g, 1.00 mmol) in neat acetic acid (0.172 mL,
3.00 mmol) was stirred at room temperature for 4 days. The reac-
tion mixtures were then concentrated in vacuo with toluene
(3 ꢁ 3 mL). Crude products were chromatographed on a silica gel
column with methylene chloride–acetone (10:1, v/v) to give the
protected 2-amino-1,3-dihydroxypropylphosphonates 8.
An efficient synthetic route to all four enantiomers of diethyl
3-acetoxymethyl-1-[tert-butoxycarbonyl]aziridine-2-yl-2-phos-
phonate has been described. Readily available aziridinephospho-
nates (1S,2S,10R)-7a and (1R,2S,10R)-7c and their enantiomers
(1R,2R,10S)-7b and (1S,2R,10S)-7d were selected as starting materi-
als. The three-step procedure relies on the regioselective aziridine
ring opening with acetic acid (in dichloromethane or neat) at the

204
A. E. Wróblewski, J. Drozd / Tetrahedron: Asymmetry 22 (2011) 200–206
4.1.1. Diethyl (1S,2S)-3-acetoxy-1-hydroxy-2-[(R)-1-
layer was extracted with CH2Cl2 (5 ꢁ 5 mL). The combined organic
extracts were washed with brine (10 mL), dried over anhydrous
MgSO4, filtered and concentrated in vacuo. Purification by silica
gel chromatography (CH2Cl2/MeOH, 200:1,v/v) gave aziridine-2-
phosphonates 10 as slightly yellowish oils.
phenylethylamino]propylphosphonate 8a
From
0.728 mmol) phosphonate (1S,2S,10R)-8a (0.241 g, 89%) was ob-
tained as a colourless oil. IR (film): = 3283, 3027, 2980, 2930,
aziridinephosphonate
(1S,2S,10R)-7a
(0.228 g,
m
2869, 1740, 1451, 1368, 1233, 1030, 970, 765, 703 cmꢀ1
.
½
a 2D0
ꢂ
¼ þ70:8 (c 1.13, CHCl3). 1H NMR (300 MHz, CDCl3): d = 7.35–
4.2.1. Diethyl (2R,3S)-3-acetoxymethyl-1-[(R)-1-phenylethyl]
aziridin-2-yl-2-phosphonate 10a
7.21 (m, 5H), 4.31 (dd, J = 11.7, 5.7 Hz, 1H, HaCHb), 4.23 (ddd,
J = 11.7, 3.9, 1.2 Hz, 1H, HaCHb), 4.13–3.98 (m, 4H, CH2OP), 3.94
(q, J = 6.6 Hz, 1H, HCCH3), 3.80 (dd, J = 6.0, 5.7 Hz, 1H, HCP), 2.97
(dtd, J = 9.6, 5.7, 5.7, 3.9 Hz, 1H, HCN), 2.06 (s, 3H) 1.38 (d,
J = 6.6 Hz, 3H, HCCH3), 1.22 and 1.21 (2 ꢁ t , J = 7.1 Hz, 6H,
CH3CH2OP). 13C NMR (75.5 MHz, CDCl3): d = 170.8, 143.9, 128.6,
127.3, 126.8, 66.1 (d, J = 166.7 Hz, CP), 63.3 (d, J = 7.2 Hz, CCCP),
62.5 and 62.3 (2 ꢁ d, J = 7.2 Hz, CH3CH2OP), 55.2, 53.6 (d,
J = 3.2 Hz, CCP), 25.1, 21.1, 16.6 (2 ꢁ d, J = 5.7 Hz, CH3CH2OP). 31P
NMR (121.5 MHz, CDCl3): d = 23.65. Anal. Calcd for C17H28NO6P:
C, 54.69; H, 7.56; N, 3.75. Found: C, 54.40; H, 7.64; N, 3.66.
From phosphonate (1S,2S,10R)-8a (0.142 g, 0.38 mmol) cis-aziri-
dine-2-phosphonate (2R,3S,10R)-10a (0.126 g, 93%) was obtained.
IR (film):
m = 2978, 2930, 2869, 1741, 1452, 1372, 1252, 1029,
967, 760, 702 cmꢀ1
.
½
a 2D0
ꢂ
¼ þ16:8 (c 1.55, CHCl3). 1H NMR
(300 MHz, CDCl3): d = 7.40–7.24 (m, 5H), 4.50 (dd, J = 12.0,
4.8 Hz, 1H, HaCHb), 4.39 (ddd, J = 12.0, 7.8, 0.6 Hz, 1H, HaCHb),
3.94 (dq, J = 7.5, 7.2 Hz, 2H, CH2OP), 3.78 (ddq, J = 10.1, 7.2,
6.9 Hz, 1H, HaCHbOP), 3.51 (ddq, J = 10.1, 7.2, 7.9 Hz, 1H, HaCHbOP),
2.53 (q, J = 6.6 Hz, 1H, HCCH3), 2.21 (dtd, J = 7.8, 6.9, 6.9, 4.8 Hz, 1H,
HCCP), 2.12 (s, 3H), 1.67 (dd, J = 15.6, 6.9 Hz, 1H, HCP), 1.49 (d,
J = 6.6 Hz, 3H, HCCH3), 1.22 and 1.01 (2 ꢁ t, J = 7.2 Hz, 6H,
CH3CH2OP). 13C NMR (75.5 MHz, CDCl3): d = 170.9, 142.8, 128.5,
127.7, 127.4, 71.4 (d, J = 6.0 Hz, CH3CPh), 63.7 (s, CH2OAc), 62.5
and 61.9 (2 ꢁ d, J = 6.0 Hz, CH3CH2OP), 42.7 (d, J = 5.4 Hz, CCP),
36.1 (d, J = 214.8 Hz, CP), 23.0 (s, CH3CPh), 21.2 (s, CH3CO), 16.6
and 16.4 (2 ꢁ d, J = 6.3 Hz, CH3CH2OP). 31P NMR (121.5 MHz,
CDCl3): d = 22.25. Anal. Calcd for C17H26NO5P: C, 57.46; H, 7.37;
N, 3.94. Found: C, 57.35; H, 7.34; N, 4.12.
4.1.2. Diethyl (1R,2R)-3-acetoxy-1-hydroxy-2-[(S)-1-
phenylethylamino]propylphosphonate 8b (ent-8a)
From aziridinephosphonate (1R,2R,10S)-7b (0.267 g, 0.852
mmol) phosphonate (1R,2R,10S)-8b (0.273 g, 86%) was obtained as
a colourless oil. ½a D20
¼ ꢀ69:8 (c 1.06, CHCl3). Anal. Calcd for
ꢂ
C
17H28NO6P: C, 54.69; H, 7.56; N, 3.75. Found: C, 54.67; H, 7.82; N,
3.71.
4.2.2. Diethyl (2S,3R)-3-acetoxymethyl-1-[(S)-1-phenylethyl]
aziridin-2-yl-2-phosphonate 10b (ent-10a)
4.1.3. Diethyl (1R,2S)-3-acetoxy-1-hydroxy-2-[(R)-1-
phenylethylamino]propylphosphonate 8c
From phosphonate (1R,2R,10S)-8b (0.15 g, 0.40 mmol) cis-aziri-
From aziridinephosphonate (1R,2S,10R)-7c (0.259 g, 0.827
dine-2-phosphonate (2S,3R,10S)-10b (0.131 g, 92%) was obtained.
mmol) phosphonate (1R,2S,10R)-8c (0.188 g, 61%) was obtained as
½
a 2D0
ꢂ
¼ ꢀ16:4 (c 0.78, CHCl3). Anal. Calcd for C17H26NO5P: C,
a colourless oil. IR (film):
m = 3312, 2980, 2927, 2867, 1739, 1452,
1369, 1234, 1031, 970, 764, 703 cmꢀ1. ½a D20
¼ þ66:4 (c 1.56, CHCl3).
ꢂ
57.46; H, 7.37; N, 3.94. Found: C, 57.27; H, 7.55; N, 3.91.
1H NMR (300 MHz, CDCl3): d = 7.35–7.24 (m, 5H), 4.31 (d,
J = 6.0 Hz, 2H, HaCHb), 4.25–4.08 (m, 4H, CH2OP), 4.02 (q,
J = 6.6 Hz, 1H, HCCH3), 3.82 (dd, J = 6.0, 5.7 Hz, 1H, HCP), 3.01
(dtd, J = 25.6, 6.0, 6.0, 5.7 Hz, 1H, HCN), 2.07 (s, 3H), 1.38 (d,
J = 6.6 Hz, 3H, HCCH3), 1.33 and 1.29 (2 ꢁ t, J = 7.1 Hz, 6H,
CH3CH2OP). 13C NMR (75.5 MHz, CDCl3): d = 170.9, 144.3, 128.8,
127.6, 127.1, 67.3 (d, J = 160.1 Hz, CP), 63.7 (d, J = 6.9 Hz,
CH3CH2OP), 63.4 (d, J = 2.9 Hz, CCCP), 62.4 (d, J = 7.4 Hz,
CH3CH2OP), 55.6, 55.5 (d, J = 2.6 Hz, CCP), 25.3, 21.3, 16.9 and
16.7 (2 ꢁ d, J = 5.7 Hz, CH3CH2OP). 31P NMR (121.5 MHz, CDCl3):
d = 23.35. Anal. Calcd for C17H28NO6P: C, 54.69; H, 7.56; N, 3.75.
Found: C, 54.41; H, 7.83; N, 3.50.
4.2.3. Diethyl (2S,3S)-3-acetoxymethyl-1-[(R)-1-phenylethyl]
aziridin-2-yl-2-phosphonate 10c
From phosphonate (1R,2S,10R)-8c (0.210 g, 0.562 mmol) trans-
aziridine-2-phosphonate (2S,3S,10R)-10c was obtained as a 2:1
mixture of N-invertomers (0.180 g, 90%). IR (film):
2929, 2870, 1743, 1449, 1372, 1236, 1030, 969, 760, 702 cmꢀ1
¼ þ41:7 (c 1.32, CHCl3). Anal. Calcd for C17H26NO5P: C,
57.46; H, 7.37; N, 3.94. Found: C, 57.61; H, 7.64; N, 3.75.
m = 2979,
.
½ ꢂ
a 2D0
4.2.3.1. Major invertomer (1R,2S,3S,10R)-13c.
1H NMR
(600 MHz, CDCl3): d = 7.45–7.18 (m, 5H), 4.31–4.21 (m, 1H, HaCHb),
4.07–3.97 (m, 1H, HaCHb), 4.02 (q, J = 6.3 Hz, 1H, HCCH3), 4.07–3.96
(m, 2H, CH2OP), 3.65–3.53 (m, 1H, HaCHbOP), 3.49–3.36 (m, 1H,
HaCHbOP), 2.70–2.62 (m, 1H, HCCP), 2.09 (s, 3H), 1.94 (dd,
J = 15.9, 3.6 Hz, 1H, HCP), 1.37 (d, J = 6.3 Hz, 3H, HCCH3), 1.26 and
0.84 (2 ꢁ t, J = 7.2 Hz, 6H, CH3CH2OP). 13C NMR (75.5 MHz, CDCl3):
d = 170.6, 144.8, 128.1, 126.9, 126.8, 66.3 (s, CH2OAc), 62.2 and
61.8 (2 ꢁ d, J = 6.0 Hz, CH3CH2OP), 60.8 (d, J = 8.3 Hz, CH3CPh),
40.5 (s, CCP), 33.7 (d, J = 182.0 Hz, CP), 25.3 (s, CH3CPh), 21.0 (s,
CH3CO), 16.6 and 16.0 (2 ꢁ d, J = 6.8 Hz, CH3CH2OP). 31P NMR
(121.5 MHz, CDCl3): d = 23.82.
4.1.4. Diethyl (1S,2R)-3-acetoxy-1-hydroxy-2-[(S)-1-
phenylethylamino]propylphosphonate 8d (ent-8c)
From aziridinephosphonate (1S,2R,10S)-7d (0.360 g, 1.15 mmol)
phosphonate (1S,2R,10S)-8d (0.267 g, 62%) was obtained as a col-
ourless oil.
17H28NO6P: C, 54.69; H, 7.56; N, 3.75. Found: C, 54.51; H, 7.60;
N, 3.46.
½
a 2D0
ꢂ
¼ ꢀ65:5 (c 1.30, CHCl3). Anal. Calcd for
C
4.2. Intramolecular cyclisation of phosphonates 8 (general
procedure)
4.2.3.2. Minor invertomer (1S,2S,3S,10R)-13c.
1H NMR
(600 MHz, CDCl3): d = 7.45–7.18 (m, 5H), 4.25–4.15 (m, 1H, HaCHb),
4.15–4.05 (m, 1H, HaCHb), 4.25–4.15 and 4.10–4.00 (m, 4H, CH2OP),
3.23 (q, J = 6.3 Hz, 1H, HCCH3), 2.80–2.72 (m, 1H, HCCP), 1.62 (s,
3H), 1.77 (dd, J = 19.5, 2.7 Hz, 1H, HCP), 1.46 (d, J = 6.3 Hz, 3H,
HCCH3), 1.36 and 1.26 (2 ꢁ t, J = 7.2 Hz, 6H, CH3CH2OP). 13C NMR
(75.5 MHz, CDCl3): d = 170.3, 144.2, 128.3, 126.8, 126.3, 63.0 and
62.9 (2 ꢁ d, J = 6.0 Hz, CH3CH2OP), 61.8 (d, J = 8.3 Hz, CH3CPh),
60.1 (d, J = 1.5 Hz, CH2OAc), 39.7 (d, J = 6.8 Hz, CCP), 36.2 (d,
To a solution of phosphonates 8 (0.373 g, 1.00 mmol) in CH2Cl2
(4 mL) under an argon atmosphere at ꢀ70 °C was added NEt3
(0.70 mL, 5.0 mmol). The dark-yellow mixture was stirred for
15 min at ꢀ70 °C and then treated with mesyl chloride (0.24 mL,
3.0 mmol). The mixture was allowed to warm to room tempera-
ture, stirred overnight and then quenched with 3 mL of saturated
NaHCO3 solution. The organic layer was separated and the aqueous

A. E. Wróblewski, J. Drozd / Tetrahedron: Asymmetry 22 (2011) 200–206
205
J = 214.4 Hz, CP), 25.3 (s, CH3CPh), 20.4 (s, CH3CO), 16.6 (d,
J = 6.8 Hz, CH3CH2OP). 31P NMR (121.5 MHz, CDCl3): d = 22.59.
4.3.4. Diethyl (2R,3R)-3-acetoxymethyl-1-(tert-butoxycarbonyl)
aziridin-2-yl-2-phosphonate 11d (ent-11c)
From a mixture of N-invertomers of aziridine-2-phosphonate
(2R,3R,10S)-10d (0.102 g, 0.273 mmol) N-Boc-protected azi-
ridinephosphonate (2R,3R)-11d (0.083 g, 86%) was obtained as a
4.2.4. Diethyl (2R,3R)-3-acetoxymethyl-1-[(S)-1-phenylethyl]
aziridin-2-yl-2-phosphonate 10d (ent-10c)
colourless oil.
14H26NO7P: C, 47.86; H, 7.46; N, 3.99. Found: C, 47.90; H, 7.68;
N, 3.89.
½
a 2D0
ꢂ
¼ ꢀ38:7 (c 1.37, CHCl3). Anal. Calcd for
From phosphonate (1S,2R,10S)-8d (0.342 g, 0.916 mmol) trans-
aziridine-2-phosphonate (2R,3R,10S)-10d was obtained as a 2:1
C
mixture of N-invertomers (0.294 g, 90%). ½a D20
¼ ꢀ42:7 (c 1.24,
ꢂ
CHCl3). Anal. Calcd for C17H26NO5P: C, 57.46; H, 7.37; N, 3.94.
Found: C, 57.24; H, 7.65; N, 3.85.
Acknowledgments
Financial support from the Medical University of Łódz´ (502-13-
772) is gratefully acknowledged. The authors wish to express their
gratitude to Mrs. Edyta Grzelewska for excellent technical assis-
tance. A part of this project was conducted by Miss Sylwia Bara-
nowska. The principal investigator thanks Dr. Dorota G.
Piotrowska for many helpful discussions and her involvement in
the preparation of the final version of the manuscript.
4.3. Hydrogenolysis of aziridine-2-phosphonates 10a–d (general
procedure)
A
solution of aziridine-2-phosphonates 10a–d (0.178 g,
0.500 mmol) in ethanol (4 mL) containing Boc2O (0.218 g,
1.00 mmol) was stirred under an atmospheric pressure of hydro-
gen over 10% Pd–C (50 mg) at room temperature for 7 hours. The
suspension was filtered through a layer of Celite, the solution
was concentrated and chromatographed on a silica gel column
with CH2Cl2–MeOH (200:1 and 100:1, v/v).
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0.315 mmol) N-Boc-protected aziridinephosphonate (2R,3S)-11a
(0.098 g, 89%) was obtained as colourless oil. IR (film):
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(2R,3S,10R)-10a
(0.112 g,
a
m
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CH3CH2OP). 13C NMR (75.5 MHz, CDCl3): d = 170.8, 160.5, 82.8,
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47.56; H, 7.76; N, 3.89.
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From
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(2S,3R,10S)-10b
(0.126 g,
0.355 mmol) N-Boc-protected aziridinephosphonate (2S,3R)-11b
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ꢂ
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colourless oil. IR (film):
m = 2983, 2934, 1730, 1443, 1370, 1294,
1318, 1233, 1158, 1028, 973 cmꢀ1. ½a D20
¼ þ37:8 (c 1.12, CHCl3).
ꢂ
1H NMR (300 MHz, CDCl3): d = 4.32–4.27 (m, 2H, HaCHb), 4.28–
4.14 (m, 4H, CH2OP), 3.05 (dtd, J = 7.8, 4.2, 4.2, 3.6 Hz, 1H, HCCP),
2.57 (dd, J = 17.7, 3.6 Hz, 1H, HCP), 2.07 (s, 3H), 1.47 (s, 9H,
(CH3)3C), 1.37 (t, J = 7.2 Hz, 6H, CH3CH2OP). 13C NMR (75.5 MHz,
CDCl3): d = 170.1, 158.4 (d, J = 7.5 Hz, CNCP), 82.6, 63.4 and 62.9
(2 ꢁ d, J = 6.0 Hz, CH3CH2OP), 61.6, 38.5 (d, J = 2.3 Hz, CCP), 32.9
(d, J = 197.7 Hz, CP), 28.1, 21.0, 16.7 and 16.6 (2 ꢁ d, J = 6.0 Hz,
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7.23; N, 3.94.
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